Characterization of a recombinant factor IX molecule fused to coagulation factor XIII-B subunit
© 2023 John Wiley & Sons Ltd..
INTRODUCTION AND AIM: Severe haemophilia B (HB) is characterized by spontaneous bleeding episodes, mostly into joints. Recurrent bleeds lead to progressive joint destruction called haemophilic arthropathy. The current concept of prophylaxis aims at maintaining the FIX level >3-5 IU/dL, which is effective at reducing the incidence of haemophilic arthropathy. Extended half-life FIX molecules make it easier to achieve these target trough levels compared to standard FIX concentrates. We previously reported that the fusion of a recombinant FIX (rFIX) to factor XIII-B (FXIIIB) subunit prolonged the half-life of the rFIX-LXa-FXIIIB fusion molecule in mice and rats 3.9- and 2.2-fold, respectively, compared with rFIX-WT. However, the mechanism behind the extended half-life was not known.
MATERIALS AND METHODS: Mass spectrometry and ITC were used to study interactions of rFIX-LXa-FXIIIB with albumin. Pharmacokinetic analyses in fibrinogen-KO and FcRn-KO mice were performed to evaluate the effect of albumin and fibrinogen on in-vivo half-life of rFIX-LXa-FXIIIB. Finally saphenous vein bleeding model was used to assess in-vivo haemostatic activity of rFIX-LXa-FXIIIB.
RESULTS AND CONCLUSION: We report here the key interactions that rFIX-LXa-FXIIIB may have in plasma are with fibrinogen and albumin which may mediate its prolonged half-life. In addition, using the saphenous vein bleeding model, we demonstrate that rFIX-FXIIIB elicits functional clot formation that is indistinguishable from that of rFIX-WT.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
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| Enthalten in: |
Haemophilia : the official journal of the World Federation of Hemophilia - 29(2023), 6 vom: 04. Nov., Seite 1483-1489 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Desage, Stephanie [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.11.2023 Date Revised 05.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/hae.14855 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM362046735 |
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| 245 | 1 | 0 | |a Characterization of a recombinant factor IX molecule fused to coagulation factor XIII-B subunit |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 John Wiley & Sons Ltd. | ||
| 520 | |a INTRODUCTION AND AIM: Severe haemophilia B (HB) is characterized by spontaneous bleeding episodes, mostly into joints. Recurrent bleeds lead to progressive joint destruction called haemophilic arthropathy. The current concept of prophylaxis aims at maintaining the FIX level >3-5 IU/dL, which is effective at reducing the incidence of haemophilic arthropathy. Extended half-life FIX molecules make it easier to achieve these target trough levels compared to standard FIX concentrates. We previously reported that the fusion of a recombinant FIX (rFIX) to factor XIII-B (FXIIIB) subunit prolonged the half-life of the rFIX-LXa-FXIIIB fusion molecule in mice and rats 3.9- and 2.2-fold, respectively, compared with rFIX-WT. However, the mechanism behind the extended half-life was not known | ||
| 520 | |a MATERIALS AND METHODS: Mass spectrometry and ITC were used to study interactions of rFIX-LXa-FXIIIB with albumin. Pharmacokinetic analyses in fibrinogen-KO and FcRn-KO mice were performed to evaluate the effect of albumin and fibrinogen on in-vivo half-life of rFIX-LXa-FXIIIB. Finally saphenous vein bleeding model was used to assess in-vivo haemostatic activity of rFIX-LXa-FXIIIB | ||
| 520 | |a RESULTS AND CONCLUSION: We report here the key interactions that rFIX-LXa-FXIIIB may have in plasma are with fibrinogen and albumin which may mediate its prolonged half-life. In addition, using the saphenous vein bleeding model, we demonstrate that rFIX-FXIIIB elicits functional clot formation that is indistinguishable from that of rFIX-WT | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Leuci, Alexandre |e verfasserin |4 aut | |
| 700 | 1 | |a Enjolras, Nathalie |e verfasserin |4 aut | |
| 700 | 1 | |a Holle, Lori A |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Sneha |e verfasserin |4 aut | |
| 700 | 1 | |a Delavenne, Xavier |e verfasserin |4 aut | |
| 700 | 1 | |a Wolberg, Alisa S |e verfasserin |4 aut | |
| 700 | 1 | |a Biswas, Arijit |e verfasserin |4 aut | |
| 700 | 1 | |a Dargaud, Yesim |e verfasserin |4 aut | |
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